Project Summary: Environmental factors, especially microbiota, modify genetic susceptibility to many chronic diseases. The NGRRC provides an essential resource for local, regional and national multidisciplinary investigators to explore the hypothesis that residental bacteria strongly influence physiologic processes in normal hosts and pathogenic inflammatory, metabolic and neoplastic responses in genetically susceptible hosts. This unit provides a resource for broadly based NIH-funded investigators to examine physiologic and pathophysiologic differences in germ-free (GF, sterile) vs. gnotobiotic (selectively colonized) vs. specific pathogen free mice of different genetic backgrounds, to explore the functional alterations of normal vs. dysbiotic microbiota in murine models and human diseases, and to define the functional relevance of bacterial genes. The microbiota can be precisely manipulated by colonizing GF mice with single or multiple resident or pathogenic bacterial, viral or fungal strains using isogenic wild type or mutated strains. In addition, fecal transplants can be performed from murine models or human donors. Aims: 1. Provide GF and gnotobiotic WT and mutant mice, their tissues and cells to NIH-funded investigators. 2. Derive additional GF mouse strains for NIH -funded investigators. 3. Support pilot studies for new investigators to generate preliminary data for NIH grant applications. 4. Train personnel to develop murine and zebrafish gnotobiotic facilities in other institutions. 5. Develop and characterize complex human and murine microbial communities and a library of bacteria strains to facilitate reproducible results in gnotobiotic studies (Research Component). We provide a unique and essential resource for a multidisciplinary group of NIH-funded investigators to study physiologic and patho-physiologic functions of normal and dysbiotic resident bacteria, with particular emphasis on gene/environ-mental interactions in genetically altered gnotobiotic mice (transgenic, knockout or spontaneously mutated) with altered physiology and disease phenotypes. In the past 5 years of funding, the NGRRC provided 8279 gnotobiotic mice to 101 investigators in 49 institutions. 68 funded NIH grants (in 12 Institutes) by 51 investigators as well as 63 grants by other funding agencies depend on gnotobiotic mice from the NGRRC.